title: The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid beta peptides in an in vitro model of the blood-brain barrier cells.
abstract: The metabolism of amyloid beta peptide (A beta) in the brain is crucial to the pathogenesis of Alzheimer disease. A body of evidence suggests that A beta is actively transported from brain parenchyma to blood across the blood-brain barrier (BBB), although the precise mechanism remains unclear. To unravel the cellular and molecular mechanism of A beta transport across the BBB, we established a new in vitro model of the initial internalization step of A beta transport using TR-BBB cells, a conditionally immortalized endothelial cell line from rat brain. We show that TR-BBB cells rapidly internalize A beta through a receptor-mediated mechanism. We also provide evidence that A beta internalization is mediated by LRP1 (low density lipoprotein receptor-related protein 1), since administration of LRP1 antagonist, receptor-associated protein, neutralizing antibody, or small interference RNAs all reduced A beta uptake. Despite the requirement of LRP1-dependent internalization, A beta does not directly bind to LRP1 in an in vitro binding assay. Unlike TR-BBB cells, mouse embryonic fibroblasts endogenously expressing functional LRP1 and exhibiting the authentic LRP1-mediated endocytosis (e.g. of tissue plasminogen activator) did not show rapid A beta uptake. Based on these data, we propose that the rapid LRP1-dependent internalization of A beta occurs under the BBB-specific cellular context and that TR-BBB is a useful tool for analyzing the molecular mechanism of the rapid transport of A beta across BBB.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamada
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Chiori
authors.initials: C
authors.lastname: Yabuki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nagae
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Basak
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D021381:Protein Transport; D051381:Rats; D011973:Receptors, LDL / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D003094:Collagen